MX2011005943A - Thieno [3, 2-c] pyridine derivatives as kinase inhibitors for use in the treatment of cancer. - Google Patents

Abstract

Compounds that inhibit protein kinases such as Aurora-kinases and the VEGFR and PDGFR families of kinases, with an improved safety profile due to low CYP3A4 inhibition, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.

Description

DERIVATIVES OF TI ??? G3.2-? 1 PI RIDI N AS LIKE INHIBITORS OF KINASE TO BE USED IN THE TREATMENT OF CANCER Field of the Invention The present invention pertains to compounds that inhibit protein kinases, such as Aurora kinases and the VEGFR and PDGFR kinase families, and which have an improved safety profile due to a low inhibition of CYP3A4, also refers to compositions that contain the compounds, and methods for treating diseases using the compounds.

Sequence Listing The present application contains a Sequence Listing that has been presented through EFS-Web and is incorporated in its entirety to the present invention as a reference. The ASCII copy, created on March 5, 2010, is named 9714WO01.txt, and is 943 bytes in size.

Background of the Invention Mitosis is a process through which a complete copy of a duplicated genome is secreted through the microtubule wheel apparatus into two daughter cells. The Aurora kinases, key mitotic regulators required for genome stability, have been found to be overexpressed in human tumors. Therefore there is a existing need in the therapeutic techniques for compounds that inhibit Aurora-kinase compositions, which comprise inhibitors and methods for treating diseases during which Aurora-kinases are deactivated or over-expressed.

Reversible protein phosphorylation is one of the primary biochemical mechanisms that transmit eukaryotic cell signaling. This reaction is catalyzed by protein kinases that transfer the group of ATP g-phosphate to hydroxyl groups in target proteins. There are 518 of said enzymes in the human genome of which -90 selectively catalyze the phosphorylation of the tyrosine hydroxyl groups. Cytosolic tyrosine kinases reside intracellularly, whereas receptor tyrosine kinases (RTKs) possess both extracellular and intracellular domains and function as cell surface receptors that span the membrane. Therefore, RTKs transmit cellular responses to environmental signals and facilitate a wide range of cellular processes including proliferation, migration and survival.

The RTK signaling pathways are normally regulated at a high level, yet their over-activation has been shown to promote the growth, survival and metastasis of cancer cells. RTK signaling occurs through over-expression and gene mutation and has been correlated with the progress of various human cancers.

The VEGF receptor family (VEGFR) consists of three RTKs, KDR (receptor containing the kinase insert domain; VEGFR2), FLT1 (tyrosine kinase Ems type; VEGFR1), and FLT4 (VEGFR3). These receptors transmit the biological function of vascular endothelial growth factors (VEGF-A, -B, -C, -D, -E, and placental growth factor (PIGF)), a family of homodimeric glycoproteins that bind to VEGF receptors. with different affinities.

KDR is the major transmitter of the mitogenic, angiogenic and permeability enhancing effects of VEGF-A, hereinafter referred to as VEGF. Many different cell types have the ability to produce VEGF, their biological activity being predominantly limited to the vasculature by means of the selective endothelial cell expression of KDR. Not surprisingly, the VEGF / KDR axis is a primary transmitter of angiogenesis, the medium through which new blood vessels are formed from preexisting vessels.

FLT1 binds VEGF, VEGF-B and the placental growth factor. FLT1 is expressed on the surface of smooth muscle cells, monocytes and hematopoietic stem cells, in addition to endothelial cells. Activation of FLT1 signaling results in the metabolization of endothelial progenitor cells derived from bone marrow that they are recruited into tumors, where they contribute to the formation of new blood vessels.

FLT4 transmits the signaling of VEGF-C and VEGF-D, which transmits the formation of lymphatic vessels associated with tumor (lymphangiogenesis). Lymphatic vessels are one of the routes through which cancer cells spread from solid tumors during metastasis.

The PDGF receptor family (PDGFR) consists of five RTKs, PDGFR-a and -b, CSF1R, KIT, and FLT3.

The a and b isoforms of platelet-derived growth factor (PDGF) receptors occur as a / b homodimers or heterodimers and are most commonly found on the surface of fibroblasts and smooth muscle cells. PDGFR-b contributes to tumor angiogenesis through the proliferation and migration of pericytes, the peri-endothelial cells that associate with and stabilize immature blood vessels. In gliomas, autocrine PDGFR stimulation, led by the co-expression of PDGF and PDGF receptors, transmits the proliferation and survival of tumor cells.

CSF-1R is encoded by the cellular counterpart of the retroviral oncogene v-fms and is an important regulator of the development of macrophages. Macrophages are frequent components of tumor stroma and have been shown to modify the extracellular matrix in a way beneficial for growth and tumor metastasis.

KIT is expressed by hematopoietic progenitor cells, mast cells, germ cells and by pacemaker cells in the intestine (interstitial cells of Cajal). They contribute to tumor progression through two general mechanisms, called autocrine stimulation through their ligand, stem cell factor (SCT), and through mutations that result in ligand-independent kinase activity.

FLT3 is normally expressed in hematopoietic stem cells, where its interaction with the ligand with FLT3 (FL) stimulates the survival, proliferation and differentiation of the stem cell. In addition to being overexpressed in various leukemia cells, FLT3 is frequently mutated in hematological malignancies with approximately one third of patients with acute myeloid leukemia (AML) containing activation mutations.

Accordingly, identification of effective small compounds that specifically inhibit signal transduction and cell proliferation is desirable, by modulating the activity of tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation or metabolism. In particular, it may be beneficial to identify methods and compounds that specifically inhibit the function of a tyrosine kinase that is essential for angiogenic processes or the formation of vascular hyper-permeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition, as well as associated disorders.

The drugs administered are eliminated from the body either by excretion or by metabolism to one or more metabolites. One class of enzymes and metabolism that is particularly important in drug metabolism is the enzyme family of cytochrome P450 (also known as CYP or P450). There is a large family of isoenzymes that has been divided into approximately 15 subfamilies. The CYP3A subfamily, which includes CYP3A4, 3A5, 3A7 and 3A43 is responsible for the metabolism of approximately 60% of the known therapeutic drugs. CYP3A4 in particular, is the most abundant CYP isoenzyme in both the liver and the intestine, and is involved in the metabolism of more than 50% of the drugs used clinically (Cytochrome P455 3A4 Mechanism-Based Inhibition by Therapeutic Drugs. , 2005, 44, 279-304). Like all other CYP enzymes, CYP3A4 is susceptible to both reversible and pseudo-irreversible or irreversible (mechanism-based) inhibition (Time-Dependent CYP Inhibition, Expert Opin, Drug Metab, Toxicol, 2007, 3, 51-66) . Its low-level substrate specificity towards CYP enzymes susceptible to inhibition through a wide variety of drugs structurally different.

As a result of CYP inhibition, abrupt changes with an agent co-administered in a single individual can occur, leading to a substantial increase or decrease in blood and tissue concentrations of a drug or metabolite. These types of changes can alter the safety and efficacy profile of a drug in important ways, especially drugs with narrow therapeutic windows. As indicated in the FDA guidelines for the industry, a detailed evaluation of the CYP inhibition potential of all new drug candidates is required (Guide for the Industry, Drug Metabolism Studies / Drug Interaction in the Development Processes of Drugs: In Vitro Studies, US FDA April 1997).

The aspect of the drug-drug interaction is very important in oncological treatment, since patients are usually treated with multiple drugs. Therefore, reducing the risk of such interaction is an important consideration in the development of novel cancer therapeutics.

Although the thienopyridine compounds described in International Publication WO2005 / 010009 deploy a potent inhibition of Aurora kinases and PDGKR / VEGFR, they may also be inhibitors of CYP3A4. The present invention belongs to novel thienopyridines of the formula I, which they maintain a potent inhibition of both Aurora kinases and the family of kinases comprising PDGFR and VEGFR and also demonstrate a reduction of at least 10 to 30 times in the inhibition of CYP3A4. Because the compounds of the present invention have significantly reduced the inhibition of CYP3A4, they are expected to display a low drug-drug interaction reliability.

In addition to the reduction in CYP inhibition, the compounds of the present invention have proven useful in additional assays used to evaluate the ability of compounds to adapt as drug candidates. For example, the compounds of the present invention demonstrate potency in whole cell assays (e.g., in the Human Umbilical Vein Endothelial Cell (HUVEC) assay and the assay that measures histone D3 phosphorylation and polyploid induction) and adequate pharmacokinetic properties (e.g., oral clearance and oral bioavailability), in vivo efficacy (e.g., Uterine Edema model, flank and orthotic tumor models in rodents), cardiovascular safety, CNS evaluations, and gastrointestinal tests.

Brief Description of the Invention In one embodiment, the present invention provides compounds of the formula (I) where R1 is hydroxyalkyl; R2 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; Y R3 is hydrogen or alkyl.

Yet another embodiment pertains to methods for treating diseases involving the transmission, overexpression and deactivation of kinases in a mammal, wherein the methods comprise administering to a mammal a therapeutically effective amount of a compound having the formula I, where R1 is hydroxyalkyl; R2 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; Y R3 is hydrogen or alkyl.

Another modality belongs to methods to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, cancer colorectal, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferation changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, thrombus essential bocytopenia, Ewing tumor, f ibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, prostate cancer insensitive to hormones, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of origin of T cell or B cell, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, carcinoma small cell lung, solid tumors (carcinomas and sarcomas), small cell lung cancer, c stomach cancer, squamous cell carcinoma, synovium, salivary gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumors, uterine cancer and Wilm's tumor in a mammal, wherein the methods comprise administering to the same a therapeutically effective amount of a compound of formula I, alone or in combination with radiotherapy.

Another modality belongs to methods to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, leukemia acute myelocytic (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferation changes (dysplasia and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocytopenia, Ewing tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma , heavy chain disease, hemangioblast ma, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T cell or B cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myososarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer , renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, carcinoma of squamous cell, synovium, salivary gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumors, uterine cancer and Wilm's tumor in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of A / - (4 - { 4-amino-7- [1 - (2-hydroxyethyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl.} - phenyl) - / S / '- (3-fluorophenyl) u rea, alone or in combination with radiotherapy.

Another modality belongs to methods to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferation changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential bocitopenic thrombus, Ewing tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, cancer hepatocellular, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies, and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas , prostate, skin and uterus, maligni lymphoid dandies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer , osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, sinovioma, salivary gland carcinoma , thyroid cancer, Waldenstrom macroglobulinemia, testicular tumors, uterine cancer and Wilm's tumor in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of A / - (4-. {4-amino-7- [1 - (2-hydroxyethyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl}. -phenyl) -A - '- [4-difluoromethoxy] phenyl] urea , alone or in combination with radiotherapy.

Another modality belongs to methods to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, cancer colorectal, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferation changes (dysplasias and metaplasias), embryonal carcinoma, cancer endometrial, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocytopenia, Ewing tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphaniosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies, and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, cancer non-small cell lung, oligodendroglioma, oral cancer, osteogenic sarcoma ico, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, Small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovitis, salivary gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilm's tumor in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of / V- [4- (4-amino-7- { 1 - [( 2S) -2-hydroxypropyl] -1 - / - pyrazol-4-yl.} Thieno [3,2-c] pyridin-3-yl) -phenyl] -V '- (3-methylphenyl) urea, alone or in combination with radiotherapy.

Another modality belongs to methods to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, cancer colorectal, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferation changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, thrombocytopenia essential, Ewing's tumor, fib rosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies, and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate , skin and uterus, lymphoid malignancies of T cell or B cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer , oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma , seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinoma) omas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovium, salivary gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumors, uterine cancer and Wilm's tumor in a mammal, in wherein the methods comprise administering thereto a therapeutically effective amount of A- (4-. { 4-amino-7- [1 - (2-hydroxy-2-methylpropyl] -1H-pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl}. -phenyl] - A / '- (4-methoxyphenyl) urea, alone or in combination with radiotherapy.

Another modality belongs to methods to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, cancer colorectal, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferation changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, thrombocytopenia essential, Ewing's tumor, fib rosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (from Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T cell or B cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, lung cancer non-small cell, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer , papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, carcinoma, sebaceous gland, seminoma, skin cancer, lung carcinoma, small cell, solid tumors (carcinomas and sarcomas), cancer small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, carcinoma of salivary gland, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of A / - [4- (4 -amino-7- { 1 - [(2S) -2, 3-dihydroxypropyl] -1H-pyrazol-4-yl} -tiene [3,2-c] pyridin-3-yl) phenyl] -A / '- (4-methoxyphenyl) urea, alone or in combination with radiotherapy.

Another embodiment pertains to compositions comprising an excipient and a therapeutically effective amount of a compound of the formula I, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Another modality belongs to compositions that they comprise an excipient and a therapeutically effective amount of W- (4-. {4-amino-7- [1- (2-hydroxyethyl) -1 / -pyrazol-4-yl] thieno [3,2 -c] pyridin-3-yl.}. phenyl) -A '- (3-fluorophenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Another embodiment pertains to compositions comprising an excipient and a therapeutically effective amount of A- (4-. {4-amino-7- [1 - (2- h id rox i et i I) -1 H-pyrazole-4 -yl] thieno [3,2-c] pyridin-3-yl.}. phenyl) - / V '- [4- (difluoromethoxy) phenyl] urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Another embodiment pertains to compositions comprising an excipient and a therapeutically effective amount of A / - [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1 / - / - pyrazole- 4-yl] thieno [3,2-c] pyridin-3-yl) phenyl) - / V '- [3- (methoxyphenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent .

Another embodiment pertains to compositions comprising an excipient and a therapeutically effective amount of A / - (4-. {4-amino-7- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazole-4- il] thieno [3,2-c] pyridin-3-yl) phenyl) -A / '- (4-methoxyphenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Another embodiment pertains to compositions comprising an excipient and a therapeutically effective amount of a / V- [4- (4-amino-7- { 1 - [(2S) -2,3-dlhydroxypropyl] -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3 -yl) phenyl] - / V '- (4-methoxyphenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment pertains to methods for treating diseases involving transmission, overexpression and deactivation of kinases in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of a compound of the formula I, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent alone or in combination with radiotherapy.

Yet another embodiment pertains to methods for treating diseases involving transmission, overexpression and deactivation of kinases in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of W- (4-. {4-amino-7 - [1 - (2-Hyd roxyethyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl}. Phenyl) -A / '- (3-fluorophenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent alone or in combination with radiotherapy.

Still another embodiment pertains to methods for treating diseases involving the transmission, overexpression and deactivation of kinases in a mammal, wherein the methods comprise administering to it a Therapeutically effective A / - (4-. {4-amino-7- [1 - (2-hydroxyethyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl .}. phenyl) -A / '- [4- (difluoromethoxy) phenyl] urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent alone or in combination with radiotherapy.

Yet another embodiment pertains to methods for treating diseases involving the transmission, overexpression and deactivation of kinases in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of A- [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1 / - / - pyrazol-4-yl} thieno [3,2-c] pyridin-3-yl) phenyl] -A / '- ( 3-methylphenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent alone or in combination with radiotherapy.

Yet another embodiment pertains to methods for treating diseases involving the transmission, overexpression and deactivation of kinases in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of A / - (4-. {4-amino -7- [1 - (2-hydroxy-2-methylpropyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl) phenyl] - / - (4-methoxyphenyl) ) urea, and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent alone or in combination with radiotherapy.

Still another modality belongs to methods to treat diseases that involve transmission, over-expression and deactivation of kinases in a mammal, wherein the methods comprise administering thereto a therapeutically effective amount of / V- [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] - 1 H-pyrrazol-4-yl] thieno [3,2-c] pyridin-3-yl) phenyl] -A / '- (4-methoxyphenyl) urea, and a therapeutically effective amount of an additional therapeutic agent or more of an additional therapeutic agent alone or in combination with radiotherapy.

Another embodiment pertains to methods for treating pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, atypical teratoid / rhabdoid tumor pediatric of the central nervous system, pediatric bifenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of the Ewing family of tumors such as primitive roectodermal neu tumors, pediatric diffuse anaplastic Wilm tumor, Wilm tumor of pediatric favorable histology, pediatric glioblastoma, Pediatric Medulloblastoma, Pediatric Neuroblastoma, Myelomitomatosis Derived from Pediatric Neuroblastoma, Pediatric Pre-B-Cell Cancers (Such as Leukemia), Pediatric Psychosarcoma, Pediatric Rhabdoid Kidney Tumor, Pediatric Rhabdomyosarcoma rich, and pediatric T cell cancers such as lymphoma and skin cancer, where the methods They comprise administering to the mammal a therapeutically effective amount of a compound of the formula I, 0 in combination with radiotherapy.

Another embodiment pertains to methods for treating pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, atypical teratoid / rhabdoid tumor pediatric of central nervous system, pediatric bifenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of the Ewing family of tumors such as primitive neuroectodermal tumors, pediatric diffuse anaplastic Wilm tumor, Wilm's tumor of pediatric favorable histologypediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma derived myelomitomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancers such as lymphoma and skin cancer, wherein the methods comprise administering to the mammal a therapeutically effective amount of / V- (4-. {4-amino-7- [1- (2-hydroxyethyl) -1-pyrazol-4-yl ] thieno [3,2-c] pyridin-3-yl.}. phenyl) - / S '- (3-fluorophenyl) urea alone or in combination with radiotherapy.

Another embodiment pertains to methods for treating pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, atypical teratoid / rhabdoid tumor pediatric of the central nervous system, pediatric bifenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of the Ewing family of tumors such as primitive neuroectodermal tumors, pediatric diffuse anaplastic Wilm's tumor, Wilm tumor of pediatric favorable histology, pediatric glioblastoma, medulloblastoma pediatric, pediatric neuroblastoma, myelomytomatosis derived from pediatric neuroblastoma, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma ico, and pediatric T cell cancers such as lymphoma and skin cancer, wherein the methods comprise administering to the mammal a therapeutically effective amount of A / - (4-. { 4-amino-7- [1 - (2-hydroxyethyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl} phenyl) - / V '- (4- (difluoromethoxy) phenyl] urea, alone or in combination with radiotherapy.

Another embodiment pertains to methods for treating pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric central nervous system teratoid / atypical rhabdoid tumor, pediatric bifenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of the Ewing family of tumors such as primitive roectodermal neu tumors, pediatric diffuse anaplastic Wilm tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma derived myelomitomatosis, pre-cell cancers -B pediatric (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T cell cancers such as lymphoma and skin cancer, wherein the methods comprise administering to the mammal a therapeutically effective amount of A / - [4- (4-amino-7-. { 1 - [(2S) -2-hydroxypropyl] -1H-pyrazol-4-yl] thieno [3, 2-c] pi ri di? -3-i I) phen i I] -? '- (3- methylphenyl) urea, alone or in combination with radiotherapy.

Another embodiment pertains to methods for treating pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, large cell lymphoma. pediatric anaplastic, pediatric anaplastic medulloblastoma, atypical pediatric central nervous system teratoid / rhabdoid tumor, pediatric bifenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of the Ewing family of tumors such as primitive neuroectodermal tumors, pediatric diffuse anaplastic Wilm tumor, Wilm's tumor of pediatric favorable histology, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma derived myelomitomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and cancers of pediatric T cell such as lymphoma and skin cancer, wherein the methods comprise administering to the mammal a therapeutically effective amount of A / - (4-. {4-amino-7- [1 - (2-hydroxy-2- methylpropyl) -1 H- pi razo I -4- i I] thieno [3, 2-c] pi ri di n -3 i I) f e n i?] -? '- (4-methoxyphenyl) urea, alone or in combination with radiotherapy.

Another embodiment pertains to methods for treating pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, atypical teratoid / rhabdoid tumor pediatric of the central nervous system, pediatric bifenotypic acute leukemia, lymphoma of Pediatric bu rkitts, pediatric cancers of the Ewing family of tumors such as primitive neuroectodermal tumors, pediatric diffuse anaplastic Wilm tumor, Wilm tumor of pediatric favorable histology, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, myelocitomatosis derived from pediatric neuroblastoma, cancers pediatric pre-cell-B (such as leukemia), pediatric psteosarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T cell cancers such as lymphoma and skin cancer, wherein the methods comprise administering to the mammal a therapeutically effective amount of / V- [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1 / - / - pyrazol-4-yl.} thieno [3,2- c] pyridin-3-yl) -phenyl] - / V '- (4-methoxyphenyl) urea, alone or in combination with radiotherapy.

Still another modality belongs to the compounds A / - (4- { 4-amino-7- [1 - (2-hydr ox i et i I) - 1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3- il.}. phenyl) -N '- (3-fluorophenyl) urea; W- (4-. {4-amino-7- [1 - (2-hyd roxy et i I) -1 H -pyrazol-4-yl] thieno [3,2-c | pyridin-3-yl} phenyl) -A / '- [4- (difluoromethoxy) phenyl] urea; / V- [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1 H -pyrazol-4-yl} thieno [3,2-c] pyridin-3 -yl) phenyl] -A / '- (3-methylphenyl) urea; / V- (4- { 4-amino-7- [1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl} phenyl) - / V '- (4-methoxyphenyl) urea; Y A / - [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1 H -pyrazol-4-yl.} Thieno [3,2-c] pyridine -3-yl) phenyl] -A / '- (4-methoxyphenyl) urea and salts therapeutically acceptable thereof.

Still another modality belongs to A / - (4- { 4-amino-7- [1 - (2-hydroxy-I-1) -1 H-pyrazol-4-yl] -thieno [3,2-c] pyridine -3-yl.}. Phenyl] - / V '- (3-fluorophenyl) urea.

Yet another embodiment belongs to A- (4- { 4-amino-7- [1- (2-hydroxyethyl) -1 H -pyrazol-4-yl] thieno [3,2-c] pyridin-3-yl. .}. phenyl) -A / '- (4- (difluoromethoxy) phenyl] urea.

Still another embodiment pertains to A / - [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1-pyrazol-4-yl.} Thieno [3, 2-c] pyridin-3-yl) phenyl] - / V '- (3-methylphenyl) urea.

Still another embodiment belongs to N- (4- { 4-amino-7- [1 - (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl] thieno [3,2-c] pyridin-3- il.) phenyl) -A / '- (4-methoxyphenyl) urea.

Still another embodiment pertains to A / - [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1H-pyrazol-4-yl.} Thieno [3,2 -c] pyridin-3-yl) phenyl] -A / '- (4-methoxyphenyl) urea.

Still another embodiment pertains to a compound of the formula I, and therapeutically acceptable salts, prodrugs, esters, amides, prodrug salts, ester salts, and amide salts thereof.

Still another modality belongs to A / - (4- { 4-amino-7- [1 - (2-hydroxyl) -1 H-pyrazol-4-yl] thieno [3,2-c] pyrid N-3-yl.} Phenyl) -A / '- (3-fluorophenyl) urea, and therapeutically acceptable salts, prodrugs, esters, amides, salts of prodrugs, salts of esters, and salts of amides thereof.

Still another modality belongs to A / - (4- { 4-amino-7- [1 - (2-hydroxyethyl) -1H-pyrazol-4-yl] thieno [3, 2-c] pi rid i? -3-i l.} phenyl) -A / '- [4- (difluoromethoxy) phenyl] urea, and therapeutically acceptable salts, prodrugs, esters, amides, salts of prodrugs, salts of esters, and salts of amides of the same.

Still another embodiment belongs to A / - [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1H-pyrazol-4-yl.} Thieno | 3,2-c ] pyridin-3-yl) phenyl] -A / '- (3-methylphenyl) urea, and therapeutically acceptable salts, prodrugs, esters, amides, salts of prodrugs, salts of esters, and salts of amides thereof.

Still another embodiment belongs to A / - (4- { 4-amino-7- [1 - (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl] thieno [3, 2-c] pyridin-3-yl.} phenyl) - / - / - (4-methoxyphenyl) urea, and therapeutically acceptable salts, prodrugs, esters, amides, prodrug salts, ester salts, and amide salts thereof.

Still another embodiment belongs to / V- [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1H-pyrazol-4-yl.} Thieno [3 , 2-c] pyridin-3-yl) phenyl] - / v "- (4-methoxyphenyl) urea, and therapeutically acceptable salts, prodrugs, esters, amides, salts of prodrugs, salts of esters, and salts of amides of the same.

Detailed description of the invention Various portions of the compounds of the present invention are represented by identifiers (uppercase letters with numerical and / or alphabetic subscripts) and they can represent in a specific way.

This means that it will be understood that suitable valences are maintained for all parts and combinations thereof, and that monovalent portions having more than one atom are joined through their left ends.

It also means that it will be understood that a specific modality of a variable portion may be the same or different from another specific modality having the same identifier.

The term "alkoxy", as used in the present invention, refers to an alkyl group attached to the molecular portion of origin through an oxygen atom.

The term "alkyl", as used in the present invention, refers to a group derived from a saturated straight or branched chain hydrocarbon containing from one to ten carbon atoms.

The terms "halo" and "halogen", as used in the present invention, refer to F, Cl, Br, or I.

The term "haloalkoxy", as used in the present invention, refers to a haloalkyl group adhered to the molecular portion of origin through an oxygen atom.

The term "haloalkyl," as used in the present invention, refers to an alkyl group, as defined in the present invention, substituted with at least one halogen, as defined in the present invention.

The term "hydroxy," as used in the present invention, refers to an -OH group.

The term "hydroxyalkyl," as used in the present invention, refers to an alkyl group substituted with at least one hydroxy group.

The term "KDR" means a kinase insert domain receptor (a type III receptor tyrosine kinase) and is also known as FLK1, VEGFR, VEGFR2, and CD309.

The term "VEGFR" means the vascular endothelial growth factor receptor.

The term "PDGFR" means the platelet-derived growth factor receptor.

The compounds of the present invention may contain carbon atoms substituted symmetrically, in the R or S configuration, where the terms "R" and "S" are as defined in the Publication Puré Appl. Chem. (1976) 45, 13-10. Compounds having carbon atoms symmetrically substituted with equal amounts of R and S configurations are racemic in said atoms. The atoms that have an excess of one configuration with respect to another, are assigned to the excess configuration, preferably an excess of about 85% to 90%, more preferably an excess of about 95% to 99%, and even more preferably an excess greater than approximately 99%. Accordingly, the present invention it is intended to encompass racemic and diastereomeric relative and absolute mixtures of the compounds thereof.

The compounds of the present invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, where the term "E" represents higher order substituents on opposite sides of the carbon double bond -carbon and, the term "Z" represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond as determined through the Cahn-Ingold-Prelog Priority Rules. The compounds of the present invention also exist as a mixture of "E" and "Z" isomers.

The compounds of the present invention may also exist as tautomers or equilibrium mixtures thereof, wherein a proton of a compound changes from a. atom to another. Examples of tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-acid, imine-enamine, and the like.

The compounds of the present invention which contain NH, C (0) OH, OH or SH portions may be bonded to the same prodrug-forming portions. The prodrug-forming portions are eliminated by metabolic processes and release the compounds having the NH, C (0) OH, OH or SH released in vivo. The prodrugs are useful for adjusting the pharmacokinetic properties of the compounds such as solubility and / or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration and clearance range.

The metabolites of the compounds of the present invention produced through in vitro metabolic processes 0 in vivo, they may also have utility in treating diseases associated with overexpression or deactivation of protein kinases.

Certain precursor compounds that can be metabolized in vitro or in vivo to form compounds of the present invention, may also have utility for treating diseases associated with overexpression or deactivation of protein kinases.

The compounds of the present invention can exist as acid addition salts, basic addition salts or zwitterions. The salts of the compounds that have the formula 1 are prepared during their isolation or after their purification. The acid addition salts are those which are derived from the reaction of a compound of the present invention with acid. Accordingly, salts including salts of acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camforate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate , hydrochloride, hydrobromide, iodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate and undecanoate, of the compounds of the present invention, it means that they are included in it. The base addition salts of the compounds are those derived from the reaction of the compounds of the present invention with the bicarbonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.

The compounds having the formula I can be administered, for example, in the buccal, ophthalmic, oral, osmotic, parenteral (intramuscular, intraperitoneal, intrasternal, intravenous, subcutaneous), rectal, topical, transdermal, vaginal, and intra-arterial form, as well as by intra-articular injection, infusion and placement in the body, such as, for example, the vasculature.

Therapeutically effective amounts of a compound having the formula I depend on the treatment recipient, the disease treated and its severity, composition of which is included, administration time, route of administration, duration of treatment, potency, range of clearance and whether the drug is jointly administered or not. The amount of compound having formula I used to make a composition that will be administered daily to a patient in a single dose or in divided doses, is from about 0.03 to about 200 mg / kg of body weight. The single dose compositions contain these amounts or a combination of submultiples thereof.

The compounds having the formula I can be administered with or without an excipient. The excipients, include but are not limited to encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, release agents, sterilization agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.

The excipients for preparation of compositions comprising a compound having the formula I which will be administered orally, include but are not limited to agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomeros, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laureate, ethyl oleate, fatty acid esters , gelatin, oil germinated, glucose, glycerol, walnut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, coconut oil, potassium phosphate salts, starch potato, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose , surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like. The excipients for the preparation of compositions comprising a compound having the formula I which will be administered in ophthalmic, or oral form include, but are not limited to 1,3-butylene glycol, castor oil, corn oil, seed oil cotton, ethanol, sorbitan fatty acid ethers, sprouted oil, walnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. The excipients for the preparation of compositions comprising a compound having formula I which will be administered in osmotic form, include but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like. The excipients for the preparation of compositions comprising a compound having formula I, which will be administered parenterally, include but is not limited to, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, sprouted oil, walnut oil, liposomes, oleic acid, olive oil, coconut oil, Ringer's solution, safflower oil, sesame oil, soy bean oil, USP, or an isotonic sodium chloride solution, water, mixtures thereof and the like. The excipients for the preparation of compositions comprising a compound having the formula I which will be administered rectally or vaginally, include but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.

Compounds having the formula I are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotic, anti-proliferative, aurora kinase inhibitors, other apoptosis promoters (e.g., Bcl-xL , Bcl-w and Bfl-1) inhibitors, inhibitors of Bcr-Ab1 kinase, BiTE antibodies (Bi-specific T cell Engager) biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase inhibitors- 2, DVD, homologous viral leukemia oncogene receptor (ErbB2) inhibitors, growth factor inhibitors, heat shock protein inhibitors (IISP) -90, histone deacetylase inhibitors (HDAC), therapies hormonal, immunological, antibiotic inhibitors that interspersed apoptosis proteins (IAP), target kinase inhibitors, mammal of rapamycin inhibitors, kinase inhibitors, regulated with extracellular signal activated by mitogen of microRNA, multivalent binding proteins, anti- non-steroidal inflammatories (NSAIDs), poly ADP (adenosine diphosphate) ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase inhibitors (PI k), proteasome inhibitors, purine analogs, pyrimidine analogs, inhibitors of receptor tyrosine kinase, plant alkaloids, retinoids / deltoids, small inhibitory ribonucleic acids (siRNA), topoisomerase inhibitors, combinations thereof, and the like.

A BiTE antibody is a bi-speci fi c antibody that directs T-cells to link cancer cells by the simultaneous binding of two cells. The T cells subsequently attack the target cancer cell. Exemplary BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like.

SiRNAs are molecules that have endogenous RNA bases or chemically modified nucleotides. The modifications should not abolish cellular activity, but rather impart increased stability and / or increased cellular power. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, ribonucleotides containing 2'-OCH3, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides or a combination thereof. The siRNA can have different lengths (10-200 bps) and structures (hairpins, single / double strands, protuberances, notches / commissures, decoupling) and be processed in the cell to provide a silencing of the active gene. In certain embodiments, a double-stranded siRNA (dsRNA) may have the same number of nucleotides in each strand (blunt ends) or asymmetric ends (protrusions). The overhang of 1 to 2 nucleotides can be present in the sense and / or anti-sense strand, as well as present at the 5'- and / or 3'- ends of a given strand.

Multivalent binding proteins are binding proteins that comprise two or more antigen binding sites. The multivalent binding protein is preferably constructed to have three or more antigen binding sites and is generally not an antibody that occurs naturally. The term "multispecific binding protein" means a binding protein with the ability to bind two or more related or unrelated targets. Dual variable domain binding proteins (DVDs) are tetravalent or multivalent binding proteins that bind proteins that comprise two or more antigen binding sites. These DVDs can be monospecific, that is, have the ability to bind to an antigen, or muitespecific, that is, having the ability to bind two or more antigens. The DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig. Each half of an Ig DVD comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in the antigen binding per antigen binding site.

Alkylating agents include altrelamin, AMD-473, AP-5280, apaziquone, bendamustine, brostalicin, busulfan, carboquone, carmuslina (BCNU), chlorambucil, CHLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide , ifosfamide, KW-2170, Jomustine (CCNU), mefosf amide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, TREANDA (bendamustine), treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial specific receptor tyrosine kinase inhibitors (Tie-2), epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (TGFR-2) inhibitors, inhibitors of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 inhibitors (MMP-9), inhibitors of platelet-derived growth factor receptor (PDGFR), thrombospondin analogs, vascular endothelial growth factor receptor (VEGFR) receptor tyrosine kinase inhibitors and the like.

Antimetabolites include ALIMTA® (metrexed disodium, LY231514, MTA), 5-azacytidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocphosphate, cytosine arabinoid, decitabine, deferoxamine, doxifluridine , eflornithine, EICAR (5-ethynyl-1- -D-ribofuranosylimidazole-4-carboxamide), enocythabin, ethynylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan) , mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocphosphate, pyretrexol, pentostatin, raltitrexed, ribavirin, triapine, tri-metrexate, S-1, thiazofurine, tegafur, TS-1, vidarabine, UFT and the like .

Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and the like.

Inhibitors of Bcl-2 protein include AT-101 ((-) gossipol), GENASENSE® (G3139 or oblimersen (direction antisense oligonucleotide Bcl-2)), IPI-194, IPT-565, N- (4- (4 - ((4'-chloro (1,1'-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4 - (((1R) -3- (dimethylamino) -1 - ((phen Lysulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737), N- (4- (4 - ((2- (4-chlorophenyl) - 5,5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1 R) -3- (morpholin-4-yl) -1 - ((phenylsulfanyl) methyl) propyl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide (ABT-263), GX-070 (obatoclax) and similar.

Inhibitors of Bcr-Ab1 kinase include DASATINIB® (BMS-354825), GLEEVEC® (imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, RMS-387, CVT-2584, lavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX® (celceoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2- (3,4-dimethylphenyl) -1 - (4-sulfamoylphenyl-1 H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS- 57067, SC-58125, SD-8381, SVT-2016, S-2474.T-25614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), bispecific anti-HER / 2neu antibody, B7.her21gG3, trifunctional antibodies AS HER2 trifunctional, m AB AR-209, m AB 2B-1 and the like.

Inhibitors of histone deacetylase include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid, and the like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamicin, IPI-504, KOS-953, MYCOGRAB® (human recombinant antibody for HSP -90), NCS-683664, PU24FCI, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of apoptosis proteins include ApoMab (a fully human affinity-matured monoclonal antibody lgG1), TRAIL-directing antibodies or mortality receptors (e.g., pro-apoptotic receptor agonists DR4 and DR5), conatumumab, ETR2-ST01, GDC0145 , (lexatumumab), HGS-029, LBY-135, PRO-1762 and tratuzumab.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.

The mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN (nabumetone), FELDENE® (piroxicam), buprofen cream, ALEVE® * (naproxen), and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin) ), CLINORIL® (sulindaco), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin and the like.

Pole type kinase inhibitors include BI-2536 and the like.

Thrombospondin analogs include ABT-510, ABT-567, TSP-1 and the like.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZY E ™ (a ribosome that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) And Chiron, (Emeryville, CA)), axitinib (AG) -13736), AZD-2171, CP-547,632, IM-862, MACUGEM (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT ® (sunitinib, SU-11248), VEGF trap, ZACTIMA ™ (vandetanib, ZD-6474) and the like.

Antibiotics include interleave antibiotics aclarubicin, actinomycin D, amrubicin, anamicin, adriamycin, BLENOXANE (bleomycin), daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, estelalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAM PTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxin), diflomotecan, edarcain, ELLENCE® or PHARMORUBICIN® ( epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, oratecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40 specific antibodies, chTNT-1 / ?, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), specific antibodies IGF1R, lintuzumab, PANOREX® (edrecolomab), RENCAREX® ( WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab and the like.

Hormone therapies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA ™ (fedrozole), FARESTO N (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON ™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAXIS ™ (abarelix), prednisone, PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin) ), TRELSTAR® (luteinization hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.

The deltoids and retinoids include seocalcoi (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PAN RETI N® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexalorene), LGD-1550 and the like.

PARP inhibitors include ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids, include but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.

Proteosome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052, PR-171 and the like.

Immunological examples include interferons and other agents that increase immunity. Interferons include interferon alpha, interferon alfa-2a, interferon alfa-2b, interferon beta, interferon gamma-1a, ACTIMMUNE (interferon gamma-Ib), or interferon gamma-n1, combinations thereof and the like. Other agents include ALFAFERONE® (IFN-a), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileucine, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte interferon alpha, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG ™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC -CL, OVAREX® (oregovomab), pemtumomab (Y-mullMFG1), PROVENGE® (sipuleucel-T), sargaramostim, sizofilan, teceleucin, THERACYS® (Bacillus Calmette-Gucrin), ubenimex, VIRULIZIN® (immunot erapeic, Lorus Pharmaceuticals) , Z-100 (Maruyama Specific Substance (SSM)), WF-10 (Tetrachlorodecaxido (TCDO)), PROLEUKIN® (aldesleucine), ZADAXIN® (timalfasin), ZENAPAX® (daclizumab), ZE VALI N® (tiuxetan 90 Y-lbritumomab) and the like.

Biological response modifiers are agents that modify the defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them for anti-tumor activity and include krestina, lentinan, sizofiran, picibanil, PF -3512676 (CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYL ™ (triacetyluridine troxacitabine) and the like.

Purine analogues include LANVIS® (thioguanine) and PURI-NETHOL® (mercaptopurine).

Antimitotic agents include beta-globin, epothilone D (KOS-862), N- (2 - ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel) ), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunin, 2K-EPO (synthetic epothilone) and the like.

The compounds of the present invention can also be used as a radiosensitizer that increases the effectiveness of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, bractherapy, and sealed source, unsealed radiotherapy and the like.

In addition, compounds having the formula I can be combined with other chemotherapeutic agents such as ABRAXANE ™ (ABI-007), ABT-00 (farnesyl transferase inhibitor), ADVEXIN® (Ad5CM V-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly hpoli C12U, a synthetic RNA), APTOS YN® (exisulind), AREDIA® (pamidronic acid), arglabine, L-asparaginase, atamestane (1-methyl-3, 17-dione- androsta-1, 4-diene), AVAGE® (tazarotene), AVE- 8062 (combreasttin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleucine), CEPLENE® (histamine dihydrochloride), CERVARIX ® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: AD RI AM YC IN® (hydroxydoxorubicin); OR; Vincristine (ONCOVIN®); P: prednisone), CYPAT ™ (cyproterone acetate), A4P combrestatin, DAB (389) EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TransMIP- 107R ™ (diphtheria toxin), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON ™ (squalamine lactate), DI ERICINA® (T4N5 liposome lotion), discodermolide, DX- 8951Í (exatecan mesylate), enzastaurin, EPO906 (epitylyl B), GARDASIL® (quadrivalent human papillomavirus recombinant vaccine (Types 6, 11, 16, 18)), GASTRIMMUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine) , OVAX® (prostate cancer vaccine), halofuginone, hysterelin, hydroxycarbamide, ibadronic acid, IGN-101, EL-13-PE38, IL-13-PE38QQR (cintudincin besudotox), IL-3-pseudomonas exotoxin, interferon- a, interferon- ?, JUNOVAN ™ or MEPACT ™ (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate , miltefosine (hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 vaccine), ORATHECIN ™ (rubitecan), OSIDEM® (drug) cell-based antibody), OVAREX® MAb (murine monoclonal antibody), paditaxel, PANDIMEX ™ (ginseng aglycone saponins comprising 20 (S) protopanaxadiol (aPPD) and 20 (S) protopanaxatriol (aPPT)), panitumumab , PANVAC®-VF (research cancer vaccine), pegaspargase, interferon A PEG, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORI ATAÑE® (acitretin), staurosporine (Staurosporos of Streptomyces), talabostat (?? 00), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), Tamilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq (2-amino-3,4-dihydro-6-methyl-4-dihydrochloride oxo-5- (4-pyridylthio) quinazoline), TNFERADE ™ (adenovector: DNA transporter containing the gene for tumor necrosis factor-a), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A) , tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (alkaloid derivative of the celandin major plant) vitaxin (alfavbeta3 antibody), XCYTRIN® (gadolinium motexafin), XINLAY ™ (atrasentan), XYOTAX ™ (polyglumex paditaxel), YONDELIS® (trabectedin), ZD-6126, ZINECARD (dexrazoxane), ZO ETA (zolendronic acid), zorubicin and the like.

To determine the Aurora B activity of representative compounds of the present invention, the active Aurora B enzyme (recombinant residues 1 to 344) and INCENP (recombinant fusion protein GST (Upstate)) were incubated in deposits of a plate of 384 deposits. with residues 1 to 21 of the histone H3 biotinylated peptide (Upstate), 1 mM ATP, and various concentrations of inhibitors and a HEPES buffer, pH 7.4 containing MgCl2, sodium othervanadate, and Triton X-100. After 1 hour, the reaction was stopped with EDTA and Europium anti-phospho-histone H3 cryptate (Cis-Bio) and SA-APC (Phycolink, Prozyme) were added to detect the phosphopeptide. The amount of phosphorylation was determined through a proportion of fluorescence signals resolved with time at 665 nm and 615 nm. The IC50 were calculated through an exponential adjustment of the inhibition values with inhibitor concentrations using the Assay Explorer software.

To determine the Aurora A and C activity of the compounds of the present invention, the Aurora A or C Active enzyme was incubated in deposits of a 384-tank plate with biotinylated STK-2 substrate (Upstate), 1 mM ATP, and various concentrations of inhibitors in a Hepes buffer, pH 7.4 containing MgCl2, another sodiumvanadate, and Triton X-100. After 1 hour, the reaction was stopped with EDTA and Europium Criptate anti-phospho-STK antibody (Upstate) and SA-XL665 (Upstate) were added to detect the phosphopeptide. The amount of phosphorylation was determined through the proportion of fluorescence signals resolved with time at 665 nm and 615 nm. The IC50 were calculated through an exponential adjustment of the inhibition values with the concentrations of the inhibitor using the Assay Explorer software.

To determine the activity of the various kinases, an in vitro fluorescence kinase assay resolved with homogeneous time (HTRF) was used. (Mathis, G., HTRF (R) Technology, J Biomol Screen, 1999.4 (6): pp. 309-314, Alfred J. Kolb, Paul V. Kaplita, David J. Hayes, Young-Whan Park, Christine Pemell, John S. ajor and Gerard Mathis, Drug Discovery Today, 1998,3, 333-342).

For example, for KDR, cKIT, FLT1, CSF1R and FTL3, purified enzyme was mixed with 0.5 μ? of N-biotinylated substrate (Biotin-Ahx-AEEEYFFLA-amide (SEQ ID 1)), various concentrations of inhibitor in reaction buffer (50 mM HEPES, pH 7.1, 10 mM MgCl2, 2 mM MnCl2, 0.1% BSA and 1 mM DTT, final volume 40 pL), ATP (1 mM final concentration) in a black plate of 384 deposits. After 60 minutes of incubation at room temperature, the reaction was quenched by the addition of an EDTA solution damped (approximate final concentrations: 30 mM EDTA, 0.1% BSA, 0.1% Triton X-100 and 0.24M KF) and a solution of revealing agents was added to the reaction mixture (to provide 0.084 ng / streptavidin-XL deposit) -665 (Cis-Bio) and 6.5 ng / deposit of Kriptato of Europium mAb PT66-K antiphosphotyrosine). The quenched reaction was allowed to settle at room temperature for 3 hours and was subsequently read in a resolved fluorescence detector over time (InVision, Perkin-Elmer) at 620 nm and 665 nm in excited sequences. The ratio between the signal of 620 nm and 665 nm was used in the calculation of IC50.

The details for the various kinases are shown in Table I (Table 1 describes "His6" and "His (6)" as SEQ ID NO: 2) · Table 1 Table 2 and Table 3 demonstrate the utility of Examples 6 as inhibitors of multiple kinases.

Table 3 Aurora B Aurora A IC50 (μ?) ICso (μ) Example 1 0.00673 0.67542 2 0.00787 4.7431 3 0.01121 0.24831 4 0.01484 3.61985 5 0.02893 0.57014 6 0.00844 0.3572 CYP 3A4 ASSAY Assays (200 μ? _ Final volume) were carried out on NUNC polypropylene deep deposit plates in a 50 nriM potassium phosphate buffer, pH 7.4, using a microtiter plate stirrer in an incubator at a temperature of 37 ° C. Human liver microsomes harvested (BD Gentest, 50 pg / mL) were incubated with 5 concentrations of test compound (0.1 μ? To 10 μ?), 1 mM NADPH (Sigma), and 2 μ? of midazolam (Sigma). A constant amount of dimethylsulfoxide (1%) was added to the incubations with the test compounds, and each analysis was carried out in duplicate. For pre-incubation experiments (Pre), microsomes, test compounds, and NADPH were mixed and incubated 30 minutes before the addition of midazolam. For co-incubation experiments (Co), the compounds, microsomes and midazolam were mixed and the reaction initiated by the addition of NADPH to the deposits. In both protocols, the complete reaction was terminated after 10 minutes of agitation by the addition of 100 μl of a 1/1 mixture of acetonitrile and methanol containing 0.33 μ? 1-Hydroxytriazolam.

For analysis, an aliquot of each reservoir was transferred to an autosampler flask and 10 μm was injected into a Shimadzu LC-10A HPLC system equipped with a YMC-AQ column (2.0 x 50 mm). The components were separated using a gradient of 10% acetonitrile - 0.1% acetic acid to 70% acetonitrile - 0.1% acetic acid in a flow range of 0.4 mL / minute for 5 minutes. Midazolam, 1-hydroxytriazolam (internal standard), 1-hydroxydazolam and 4-hydroxymidazolam were quantified by LC-MS / MS using an LCQ Duo (ThermoFinnigan). The ratio of 1-hydroxydazolam (product CYP 3A4) and the internal standard in each concentration of the compound was used to calculate the% inhibition of activity relative to the ratio calculated for control incubations without inhibitor. In the absence of NADPH, no hydroxylation of midazolam was observed. Ketoconazole was used as a standard inhibitor, which at 0.1 μ? it produces an inhibition of 70% to 80% of CYP 3A4. The IC50 (the concentration at which 50% of the enzyme was inhibited, was calculated for Examples 1 to 5 and Example 6 (described as EXAMPLE 703 in International Publication WO 2005/10009) and shown in Table 4 that it is found below.

Table 4 The data in Tables 2, 3 and 4 illustrate the utility of the compounds of the present invention as inhibitors of multiple kinases with the added benefit of reduced CYP inhibition.

The compounds described as having a low CYP inhibition or as not inhibiting CYP, are the compounds with an IC50 of > 10 μ? in the previous trial.

The structural homology between Aurora Protein Kinases A, B and C are reported in the Mature Reviews / Cancer Publication, Vol. 4 of December 2004.

It is expected that, because the compound of the present invention inhibits the activity of Kinase-Aurora B, it may also have utility as an inhibitor of protein kinases having near structural homology to it, such as, for example, kinase. Aurora A and Kinase-Aurora C. The data for Example 1 are shown in Table 5.

Table 5 These data demonstrate the utility of Example 1 as an inhibitor of kinase-Aurora A and kinase-Aurora B and kinase-Aurora C.

Accordingly, the compounds of the present invention are expected to have utility in the treatment of diseases during which protein kinases are expressed, such as any or all members of the Aurora kinase family.

The involvement of Aurora kinase in pancreatic carcinoma cells was reported in the Publication of Zhu, J., and associates, AURKA Amplification, Chromosome Instability and Centrosomo Abnormality in Human Pancreatic Carcinoma Cells. Cancer Genet. Cytogenet., 2005. 159 (1): p. 10-17; and Li D., Zhu J., Firozí P.F, and associates. Overexpression of STK15 / BTAK / Aurora A Oncogenic Kinase in Human Pancreatic Cancer. Clin. Cancer Res. 2003; 9: 991-7.

The implication of the Aurora Kinase in non-small cell lung carcinoma is reported in the Publication of Smith, SL, and associated, Aurora B Kinase (AURKB) overexpression is frequent in Primary Non-Small Cell Lung Carcinoma, Conducted Generally of an Allele, and correlates with the Level of Genetic Instability. Br. J. Cancer, 2005. 93 (6): p. 719-729.

The involvement of Aurora Kinase in prostate cancer is reported in Chieffi Publication, P., and associates, The Expression of Aurora B Directly Correlates with Malignancy of Prostate Cancer. Prostate, 2006. 66 (3): p. 326-33; and Chieffi P., Cozzolino L., Kisslinger A., and associates. The expression of Aurora B correlates directly with Malignancy of Prostate Cancer and Influences Proliferation of Prostate Cell 2006; 66: 326-33.

The implication of the Aurora Kinase in squamous cell carcinoma of the head and neck is reported in Reiter, R., and associated publication, the RNA Expression Messenger of Kinase Aurora A correlates with Tumor Progress and Decreased Survival in Squamous Cell Carcinoma of the Head and Neck. Clin Cancer Res, 2006.12 (17): p. 5136-41.

The involvement of Cinasa Aurora in acute myeloid leukemia is reported in the Publication of Walsby E., Walsh V., Pepper C, Burnett A., and Mills K. Haematologica. May 2008; 93 (5): 662-9.

The involvement of the Aurora Kinase in breast cancer is reported in the Publications of Tanaka T., Kimura M. , Matsunaga K., Fukada D., Mori H., Okano Y., Celestial Kinase AIK1 is Overexpressed in Invasive Ductal Breast Carcinoma. Cancer Res. 1999; 59: 2041-4; Miyoshi Y., Iwao K., Egawa C, Noguchi S. Expression Association of Centrosomal Kinase STM15 / BTAK mRNA with Cromosomal Instability in Human Breast Cancers. Cancers. Int. J. Cancer 2001; 92: 370-3; Hoque A., Cárter J., Xia W., and associates, the Loss of Overexpression of Aurora A / STK15 / BTAK correlates with Transition with Ductal Carcinoma in Situ A Invasive Breast. Cancer Epidemiol. Biomarkers Prev. 2003; 12: 1518-22; Royee M.E., Xia W., Sahin A.A., and associates, Expression of STK15 / Aurora-A in Primary Breast Tumors Correlates with Nuclear Grade but Not with Prognosis. Cancer 2004; 100: 12-9; Bodvarsdottir S.K., Hilmarsdottir H., Birgisdottir V., Steinarsdottir M., Jonasson J.G., Eyfjord J. E., Amplification of Aurora-A Associated with BRCA2 Mutation in Breast Tumors. Cancer Lett 2007; 248: 96-102; Sen S., Zhou H., White R.A., Putative Serine / Threonine Kinase that Encodes the BTAK Gene on Chromosome 20q13 is Amplified and Overexpressed in Human Breast Cancer Cell Lines. Oncogene 1997; 14: 2195-200; Y. I., Yu J. C, Chen S. T., and associates, Risk of Breast Cancer Associated with Genotypic Polymorphism of the Mitosis Regulation Gene Aurora-A / STK15 / BTAK. In. J. Cancer 2005; 115: 276-83; Vidarsdottir L., Bodvarsdottir S. K., Hilmarsdottir H., Tryggvadotti r L., Eyfjord J. E., Risk of Breast Cancer Associated with AURKA 91T a Relationship of Polymorphism with BRCA Mutations. Cancer Lett 2007; 250: 206-12; Cox D. G., Hankinson S.E., Hunter D. J., Polymorphisms of the Aurka Gene (STK15 / Aurora Kinase) and Risk of Breast Cancer (United States). Cancer Causes Control 2006; 17: 81-3; and Tchatchou S., M. Wirtenberger, K. Hemminki, and associates, the Aurora A and B Kinase and the Risk of Familial Breast Cancer. Cancer Lett 2007; 247: 266-72.

The involvement of Cínasa Aurora in lung cancer is reported in the publications of Smith SL, Bowers NL, Betticher D. C, and associates, it is common the overexpression of Aurora B Kinase (AURKB) in Primary Non-Small Cell Lung Carcinoma , Generally Driven by an Allele, and Correlates with the Level of Genetic Instability. Br. J. Cancer 2005; 93: 719-29; Xu H. T., Ma L., Q. F.J., and associates, Expression of Serine Threonine Kinase 15 is Associated with a Deficient Differentiation in Carcinoma and Lung Cell Adenocarcinoma. Pathol. Int. 2006; 56: 375-80; Visc ioni B., Oudejans J. J., Vos W., Rodriguez J. A., Giaccone G. Frequent Overexpression of Aurora B Kinase, a Novel Drug Target in Patients of Non-Small Cell Lung Carcinoma Mol. Cancer Ther. 2006; 5: 2905-13; and Gu J., Gong Y., Huang M. , Lu C, Spitz M.R., Wu X. Polymorphisms of the STK15 Gene (Aurora-A) and Risk of Lung Cancer in Caucasus. Carcinogenesis 2007; 28: 350-5.

The implication of Cinasa Aurora in bladder cancer is reported in the Publications of Comperat E. Camparo P., Haus R., and associates, Aurora-A / STK-15 is a Predictive Factor for Recurrent Behavior in Non-Invasive Bladder Carcinoma: Study of 128 Cases of Non-Invasive Neoplasms. Virchows Aren 2007; 450: 419-24; Fraizer G.C., Diaz M.F., Lee LL., Grossman H.B., Sen S. The Aurora-A / STK 5 / BTAK Increases Chromosomal Instability in Bladder Cancer Cells. Int. J. Oncol. 2004; 25: 1631-9; and Sen S "Zhou H., Zhang R.D., and associates, Amplification / Over-Expression of the Mitotic Kinase Gene in Human Bladder Cancers, J. Nati. Cancer Inst. 2002; 94: 1320-9.

The implication of Aurora Kinase in esophageal cancer is reported in the Publications of Tong T., Zhong Y., Kong J., and associates, the Overexpression of Aurora-A contributes to Malignant development of human esophageal squamous cell carcinoma. Clin. Cancer Res. 2004; 10: 7304-10; Yang S.B., Zhou X.B., Zhu H.X., and associates, Amplification and Overexpression of Aurora-A in Esophageal Squamous Cell Carcinoma. Oncol. Rep. 2007; 17: 1083-8; and Kimura M.T., Morí T., Conroy J., and associates, Two Simple Nucleotide Polymorphisms of Functional Coding in STK15 (Aurora-A) Increase in a Coordinated Way the Risk of Esophageal Cancer. Cancer Res 2005; 65: 3548-54.

The involvement of Cinasa Aurora in brain cancer is reported in the Publications of Araki K., Nozaki K., Ueba T., Tatsuka M., Hashimoto N, High Expression of Aurora-B / Aurora and Protein Associated with Medium Body Type Ipil (AIM-1) in Astrocytomas. J. Neurooncol. 2004; 67: 53-64; Zeng W, F., Navaratne K., Prayson R. A., Weil R.J. Expression of Aurora B correlates with Aggressive Behavior in Glioblastoma Multiforme. J. Clin. Pathol. 2007; 60: 218-21; Reichardt W., Jung V., Brunner C, and associates, The Putative Serine Gene / Threonine Kinase STK15 on Chromosome 20q13.2 is Amplified in Human Gliomas. Oncol. Rep. 2003; 10: 1275-9; Klein A., Reichardt W., Jung V., Zang K.D., Meese E., Urbachat S. Overexpression and Amplification of Inhuman Gliomas STK15. Int. J. Oncol. 2004; 25: 1789-94; and Neben K., Korshunov A., Benner A., and associates, Microassay Based Classification for Markers of Medulloblastoma Molecular Revealed STK15 as an Independent Anticipator of Survival. Cancer Res 2004; 64: 3103-11.

The involvement of Cinasa Aurora in liver cancer is reported in the Publication of Jeng Y.M., Peng S.Y., Lin C.Y., Hsu H.C. Overexpression and Amplification of Aurora-A in Hepatocellular Carcinoma. Clin. Cancer Res. 2004; 10: 2065-71.

The involvement of Cinasa Aurora in head and neck cancer is reported in the Publications of Zhao X., Li F.C., Li Y.H., and associates, [Mutation of p53 and Overexpression of STK15 in Squamous Cell Carcinoma of the Larynx]. Zhonghua Zhong Liu Za Zhi 2005; 27: 134-7; Li FC, Li YH, Zhao X., and associates, (Elimination of p15 and p16 genes and overexpression of the STK15 gene in human laryngeal squamous cell carcinoma.) Zhonghua Yi Xue Za Zhi 2003; 83: 316-9; Reiter R., Gais P., Jutting U., and associates, the RNA Expression of the Aurora A Kinase Messenger correlates with Tumor Progress and Decreased Survival in Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res. 2006; 12: 5136-41; Qi G., Ogawa I., Kudo Y., and associates, Expression of Aurora-B and its Correlation with Cell Proliferation and Metastasis in Oral Cancer. Virchows Arch 2007; 450: 297-302; and Tatsuka M., Sato S., Kitajima S., and associates, Aurora-A Overexpression Enhances Oncogenic Transformation Transmitted by HRAS and Involved in Oral Carcinogenesis. Oncogene 2005; 4: 1122-7.

The involvement of Cinasa Aurora in thyroid cancer is reported in the Publication of Sorrentino R., Libertini S., Pallante PI, and associates, the Overexpression of Aurora B is associated with the Thyroid Carcinoma No Differentiated Phenotype and is Required for Proliferation of Thyroid Carcinoma Cells. J. Clin. Endocrinol Metab. 2005; 90: 928-35.

The involvement of Cinasa Aurora in ovarian cancer is reported in the Publications of Lassmann S., Shen Y., Jutting U., and associates, Predictive Value of Aurora-A / STK15 Expression for Patients with Late Stage Epithelial Ovarian Cancer Treatments By Adjuvant Chemotherapy. Clin Cancer Res 2007; 13: 4083-91; and Landen C.N., Jr., Lin Y.G., Immaneni A., and associates, Aurora-A kinase overexpression of centrosomal protein is associated with poor prognosis in patients with epithelial ovarian cancer. Clin. Cancer Res. 2007; 13: 4098-104.

The involvement of the Aurora Kinase in renal cancer is reported in the publication of Kurahashi T., Miyake H., Hara I., Fujisawa M. Importance of the Expression of Aurora-A in Renal Cell Carcinoma. Urol. Oncol. 2007; 25: 128-33.

The implication of the Aurora Kinase in endometrial cancer is reported in the Publication of Moreno-Bueno G., Sanchez-Estevez C, Cassia R., and associates, Differential Gene Expression Profile in Endometrial Endometrial and Non-Endometroid Carcinoma: STK1. 5 is Overexpressed Frequently and it is amplified in non-endometroid carcinomas. Cancer Res. 2003; 63: 5697-702.

The implication of Cinasa Aurora in gastric cancer is reported in the Publication of Ju H., Cho H., Kim Y.S., and associates, Functional Polymorphism 57Val > of the Aurora A Kinase Associated with Increased Risk of Progression of Gastric Cancer. Cancer Lett. 2006; 242: 273-9.

The involvement of Cinasa Aurora in colon cancer is reported in the Publications of Nishida N., Nagasaka T., Kashiwagi K., Boland CR, Goel A. Amplification of High-level copies of the Aurora-A gene is associated with Instability Phenotype Chromosomal in Human Colorectal Cancers. Cancer Biol. Ther. 2007; 6: 525-33; Bischoff J.R., Anderson L., Zhu Y., and associates, a homolog of Cinasa Aurora of Drosophila is Oncogenic and Amplified in Human Colorectal Cancers. EMBO J 1998; 17: 3052-65; Chen J., Sen S., Amos C.I., and associates, Association Between Aurora-A Kinase Polymorphisms and Age of Generation of Colorectal Cancer without Hereditary Polyposis in a Caucásea Population. Mol. Carcinog, 2007; 46: 249-56; Hienonen T., Salovaara R., Mecklin J.P., Jarvinen H., Karhu A., Aaltonen I., A. Preferential Amplification in AURKA 91A (11 c 31) in Familial Colorectal Cancers. Int. J. Cancer 2006; 118: 505-8; and Ewart-Toland A., Briassouli P., of Koning J.P., and associates, Identification of Stk6 / STK15 as a Candidate for Susceptibility Gene Low Level Penetration Tumor in Mice and Humans. Nat. Genet. 2003; 34: 403-12.

The involvement of Cinasa Aurora in cancer is reported in the Publications of Lin, Y.S., and associates, Profiles of Genetic Expression of Family Kinase. Gene Expr., 2006. 13 (1): p. 15-26; and Ewart-Toland A., Dai Q., Gao Y.T., and associates, Aurora-A / STK15 T + 91A is a Low Level General Penetration Cancer Susceptibility Gene: A Meta-Analysis of Multiple Types of Cancer. Carcinogenesis 2005; 26: 1368-73.

The involvement of KDR (VEGFR2) in cancer and studies using VEGF-directed therapy is reported in Ellis, Lee M., Hicklin, Daniel J. Targeted Therapy-VEGF: Anti-tumor Activity Mechanisms. Nature Reviews Cancer 2008; 8: 579-591.

The involvement of kinases-Aurora in bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer , stomach cancer, and thyroid cancer are reported in the Nature Reviews / Cancer Publication, Vol. 4 of December, 2004.

The compounds of the present invention can be made by synthetic chemical processes, examples of which are shown in the present invention. It will be understood that the order of the steps in the processes may vary, since the reactants, solvents and reaction conditions can be replaced by those mentioned in a specific way, and vulnerable portions can be protected and unprotected, as necessary. For example 3-bromothieno [3,2-c] pyridin-4-amine.

Protecting groups for C (0) OH portions include, but are not limited to, acetoxymethyl, to I i I, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl, diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl. , diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl, triethylsilyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl Ethoxymethyl, triphenylmethyl and the like.

Protecting groups for portions C (O) and C (0) H include, but are not limited to, 3-dioxyl ketal, diethyl ketal, dimethyl ketal, 1,3-dithi ani I keta I, O-methyloxime, O- phenyloxime and the like.

Protecting groups for NH portions include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl, formyl, methanesulfinyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, trifen the meti lo, t r i fe n i I i i, para-toluenesulfonyl and the like.

Protecting groups for OH and SH portions include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2, 2,2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2- (trimethylsilyl) ethoxycarbonyl, 2-trimethylsilylethyl, triphenyl and 1-methyl, 2- (triphenylphosphonium) ethoxycarbonyl and the like.

The following abbreviations have the meanings indicated.

ADDP means, 1 '- (azodicarbonyl) dipiperidine; AD-mix-β means a mixture of (DHQD) 2PHAL, K3Fc (CN) 6, K2C03 and K2S04); To BN means 2,2'-azobis (2-methylpropionitrile); 9-BBN means 9-borabicyclo (3.3.1) nonane; Cp means cyclopentadiene; (DHQD) 2PHAL means 1,4-phthalazinadiyl diethyl ether of hydroquinidine; DBU means 1,8-diazabicyclo (5.4.0) undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means?,? - direthylaminopyridine; DME means 1,2-dimethoxyethane; DMF means N, N-dimethylformamide; dmpe means 2-bis (dimethylphosphino) ethane; DIVISO means dimethylsulfoxide; dppa means diphenylphosphoryl azide; dppb means 1,4-bis (diphenylphosphino) butane; dppe means 1,2-bis (diphenylphosphino) ethane; dppf means 1,1'-bis (diphenylphosphino) ferrocene; dppm means 1,1-bis (diphenylphosphino) methane; EDAC means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; Fmoc means fluorenylmethoxycarbonyl; HATU means O- (7-azabenzotriazol-1-yl) -N, N ', N', N'-tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphoramide; HOAT means 1-h i d rox i-7-azabenzotriazole; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis (hexamethyldisilylamide); MP-BH3 means macroporous triethylammonium methylpolystyrene cyanoborohydride; LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TBTU means O-benzotriazol-1 -? -?,?,? ',?' - tetramethyluronium tetrafluoroborate; TDA-1 means tris (2- (2-methoxyethoxy) ethyl) amine; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; PPh3 means triphenylphosphine.

EXAMPLE 1 A / - (4- { 4-amino-7- [1- (2-hydroxyethyl) -7 H -pyrazol-4-yl] t-ene [3,2-c] pyridin-3-yl}. phenyl) -N '- (3-fluorophenyl) urea EXAMPLE 1A 3- (4-aminophenyl) -7-yodothieno [3,2-c] pyridin-4-amine To a suspension of 3-bromothieno [3,2-c] pyridin-4-amine (13.7 g, 59.7 mmol), 4- (4,4,5,5-tetramethyl-, 3,2-dioxaborolan-2 -yl) tert-butyl phenylcarbamate (20 g, 62.7 mmol), tetrakis (triphenylphosphine) palladium (0) (2.5 g, 2.1 mmol) and Na 2 CO 3 (13.3 g, 125 mmol) in tetrahydrofuran (150 mL), methanol (40 g). mL) and water (80 mL) the gases were removed, then refluxed overnight. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate and the combined organics were dried (using MgSO4), filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with 50% to 70% ethyl acetate-hexanes to provide 4- (4-aminothieno [3, 2-c] pyridin-3-yl) faith crude tert-butyl nylcarbamate. A solution of the crude product (59.7 mmol based on a 100% yield) in N, N-dimethylformamide (80 mL) was treated with N-iodosuccinimide (13.5 g, 59.7 mol added in portions) and the resulting dark solution was stirred at room temperature for 2 hours, then it was divided between water (500 mL) and ethyl acetate (100 mL) with added NaCl to facilitate the separation of the layer. The aqueous layer was extracted with additional ethyl acetate (2 x 75 mL) and the combined organics were washed with sodium thiosulfate (3 x 20 ml_) and brine (50 ml_), and subsequently dried (using MgSO 4), filtered and concentrated. The crude material was treated with TFA (20 ml_) and CH2Cl2 (5 ml_), stirred at room temperature for 2 hours, concentrated under a stream of nitrogen, then concentrated in vacuo. The solid was dissolved in water (100 ml_), treated carefully with solid Na 2 CO 3 until the gas evolution ended and filtered, washing with additional water. The collected solid was dried to provide the title compound in the form of a solid (contaminated by ca. 10% mol PPh3).

EXAMPLE 1B 2- (4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H -pyrazi-1-yl) ethanol 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2- was combined one (21 g, 238 mmol) and cesium carbonate (16 g, 49.1 mmol) in a 100 ml round bottom flask. The reaction was warmed from room temperature to 100 ° C in an oil bath, time through which the carbonate had melted and served as the solvent for the reaction, which remained as a paste. After heating for 3.5 hours, the reaction was cooled to room temperature and diluted with ethyl acetate, then filtered through Celite washing repeatedly with ethyl acetate. The filtrate was concentrated, then purified by chromatography on a Analogix (R) Intelliflash (TM) purification system using an SF60-200 g column in a flow rate of 80 mL / min, eluting as follows: 5 minutes in 20% ethyl acetate / hexanes, subsequently elevated from 40% to 90% ethyl acetate / hexanes for 35 minutes, then 100% ethyl acetate for another 20 minutes, to give the title compound.

EXAMPLE 1C 2- (4- (4-amino-3- (4-aminophenyl) thieno [3,2-c] pyridin-7-yl) -1H-pyrazol-1-yl) ethanol EXAMPLE 1A (6 g, 16.34 mmol), EXAMPLE 1B (4.8 g, 20.16 mmol), PdCI2 (dppf) (1.2 g, 1640 mmol) and sodium carbonate (4.6 g, 43.4 mmol) in tetrahydrofuran ( 400 mL), methanol (80 mL) and water (80 mL), and the gas was removed from the reaction by bubbling N2 through the mixture for 1 hour. The reaction was subsequently heated to a temperature of 80 ° C for 2 hours, subsequently allowed to cool and diluted with 300 mL of ethyl acetate. The mixture was partitioned with H20 (500 mL) and the aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered through a pad of Celite, concentrated to a total volume of about 200 mL, then allowed to settle overnight. The solid that formed was collected by filtration, providing the title compound.

EXAMPLE 1 D A / - (4- { 4-amino-7- [1 - (2-hid rox i et i I) - 1 H -pyrazol-4-yl [thieno [3,2-c] pyridin- 3-yl.} Phenyl) - / V '- (3-fluorophenyl) urea EXAMPLE 1C (2 g, 5.69 mmol) was dissolved in N, N-dimethylformamide (80 ml) and the flask was cooled in a water bath. a temperature of -20 ° C. 1-Fluoro-3-isocyanatobenzene (0.715 ml, 6.26 mmol) was added in the form of drops and the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was diluted with water (500 mL) and ethyl acetate (75 mL) and stirred to digest for 1 hour. Subsequently, the mixture was placed in a separating funnel. Subsequently the layers were allowed to separate, the lower aqueous layer was drained. Near the inferióase of the two layers, there was a significant amount of precipitate. The material and organic layer were filtered to provide a solid. The solid was rinsed with ethyl acetate and dried to provide the title compound. 1 H NMR (300 MHz, DMSO-d 6) d ppm 3.80 (q, J = 5.65 Hz, 2H) 4.23 (t, J = 5.59 Hz, 2H) 4.96 (t, J = 5.09 Hz, 1H) 5.42 (s) , 2H) 6.80 (td, J = 8.31, 2.37 Hz, 1H) 7.15 (dd, J = 8.14, 1.02 Hz, 1H) 7.32 (td, J - 8.22, 6.95 Hz, 1H) 7.41 (d, J = 8.81 Hz , 2H) 7.51 (ddd, J = 11.70, 2.37, 2.20 Hz, 1 H) 7.50 (s, 1 H) 7.61 (d, J = 8.81 Hz, 2 H) 7.91 (d, J = 1.02 Hz, 1 H) 8.05 (s, 1 H) 8.15 (d, J = 0.68 Hz, 1 H) 8.96 (s, 1H) 8.99 (s, 1 H); MS (ESI (+)) m / z 489.1 (M + H) +.

EXAMPLE 2 A / - (4- { 4-amino-7- [1 - (2-hydroxyethyl) -1 H-pyrazole-4-M] tinene [3,2-c] pyridine 3-yl.}. Phenol) -A / '- [4- (difluoromethoxy) phenyl] urea The title compound was prepared by substituting 1- (di-fluoro-methoxy) -4-isocyanatobenzene for 1-fluoro-3-isocyanatobenzene in EXAMPLE 1D, 1 H NMR (300 MHz, DMSO-de) d ppm 3.80 (q, J = 5.4 Hz, 2H) 4.23 (t, J = 5.6 Hz, 2 H) 4.95 (t, J = 5.4 Hz, 1 H) 5.41 (br s, 2 H) 7.13 (t, J = 74.4 Hz, 1 H) 7.13 (d, J = 8.8 Hz, 2 H) 7.39 (d, J = 8.5 Hz, 2H) 7.48 - 7.55 (m, 3 H) 7.61 (d, J = 8.5 Hz, 2 H) 7.90 (s, 1H) 8.05 (s, 1 H) 8.15 (s, 1 H) 8.85 (s, 1 H) 8.91 (s, 1 H); MS (ESI (+)) m / e 537 (M + H) +.

EXAMPLE 3 A / - [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1-pyrazol-4-yl.} Thieno [3,2-c] pindin-3- il) phenyl] - / v '- (3-methylphenyl) urea The title compound was prepared following the procedures of EXAMPLES 1B to 1D except that (S) -4-methyl-1,3-dioxolan-2-one was substituted for 1,3-dioxolan-2-one by and 1 - isocyanate-3-methylbenzene by 1-fluoro-3-isocyanatobenzene in EXAMPLES 1B and 1D, respectively. 1 H NMR (300 MHz, DMSO-d 6) d ppm 1.09 (d, J = 6.10 Hz, 3 H) 2.29 (s, 3 H) 4.01 - 4.12 (m, 3 H) 4.96 (d, J = 4.75 Hz, 1 H) 5.43 (s, 2H) 6.81 (d, J = 7.46 Hz, 1 H) 7.17 (t, J = 7.80 Hz, 1 H) 7.26 (app d, J = 9.15 Hz, 1 H) 7.32 (s, 1 H) 7.39 (d, J = 8.48 Hz, 2 H) 7.50 (s, 1 H) 7.61 (d, J = 8.81 Hz, 2 H) 7.90 (d, J = 0.68 Hz, 1 H) 8.05 (s, 1H ) 8.13 (d, J = 1.02 Hz, 1 H) 8.66 (s, 1 H) 8.86 (s, 1 HOUR); MS (ESI (+)) m / z 499.2 (M + H) +.

EXAMPLE 4 A / - (4- { 4-amino-7- [1- (2-hydroxy-2-methylpropyl) -1 / - pyrazol-4-yl] thieno [3,2-c] pyridin-3- M.}. Phenyl) -A / '- (4-methoxyphenyl) urea EXAMPLE 4A 2-methyl-1- (4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol A mixture of 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole (500 mg, 2.57 mmol), Cs2CO3 (840 mg, 2.57 mmol) was heated. and 2,2-dimethyloxirane (2 mL) in a sealed flask at a temperature of 120 ° C for 3 minutes with stirring in a Smith Synthesizer microwave oven (in 300 W), then it was allowed to cool and diluted with CH 2 Cl 2. The resulting suspension was filtered and the filtrate was concentrated to provide the title compound.

EXAMPLE 4B A / - (4- { 4-amino-7- [1 - (2-hydroxy-2-methylpropyl) -1 Hp \ razol-4- il [thieno [3,2-c] pyridin-3-yl) Phenyl) - S / '- (4-methoxyphenyl) urea The title compound was prepared following the procedures of EXAMPLES 1C to 1D except that EXAMPLE 4A was replaced by EXAMPLE 1B and 1-isocyanato-4-methoxybenzene per 1 -fluoro-3-isocyanatobenzene in EXAMPLES 1C and EXAMPLE 1D, respectively. 1 H NMR (300 MHz, DMSO-de) d ppm 1.12 (6 H) 3.72 (s, 3 H) 4.11 (a, 2 H) 4.76 (s, 1 H) 5.43 (s, 2 H) 6.88 (d, J = 9.15 Hz, 2 H) 7.38 (d, J = 8. 81 Hz, 4 H) 7.49 (s, 1 H) 7.60 (d, J = 8.81 Hz, 2 H) 7.89 (d, J = 0.68 Hz, 1 H) 8.06 (s, 1 H) 8.11 (d, J = 0.68 Hz, 1 H) 8.55 (s, 1H) 8.80 (s, 1H); MS (ESI (+)) m / z 529.3 (M + H) +.

EXAMPLE 5 A / - [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1 H -pyrazole-4-M.} Thieno [3,2-c] pyridine -3-yl) phenyl] -A / '- (4-methoxyphenyl) urea EXAMPLE 5A (S) -1 - ((2,2-Dimethyl-, 3-d-oxo I an-4-yl) met I) -4- (4, 4, 5, 5-tetra met I-1,3) , 2-dioxaborolan-2-yl) -1 / - / - pyrazole A mixture of (R) - (2,2-dimethyl-1,3-dioxolan) methanesulfonate was heated at a temperature of 90 ° C for 3 hours. 4-l) methyl (1.08, 5.15 mmol) 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (1 g, 5.15 mmol) and NaH (262 mg, 10.9 mmol) in N, N-dimethylformamide (25 mL), then allowed to cool to room temperature, quenched with water and extracted with ethyl acetate (3x). The combined organics were washed with brine, concentrated and the residue was purified by chromatography on an Analogix (R) Intelliflash (TM) purification system using an SF25-25 g column in a flow rate of 80 mL / minute, eluting with 0% to 30% ethyl acetate: hexanes for 30 minutes to provide the title compound.

EXAMPLE 5B (S) -1- (4- (4-amino-7- (1 - ((2,2-dimethyl-1,3-dioxolan-4-yl) methyl) -1H-pyrazol-4-yl) thieno [ 3,2-c] pyridin-3-yl) phenyl) -A / '- (4-methoxyphenyl) urea The title compound was prepared following the procedures of EXAMPLES 1C to 1D except that EXAMPLE 5A was replaced by 1B and 1-isocyanato-4-methoxybenzene by 1-fluoro-3-isocyanatobenzene in EXAMPLES 1B and 1D, respectively.

EXAMPLE 5C A / - [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1 H -pyrazol-4-yl.} Thieno [3,2-c] pyridine -3-yl) phenyl] -A / '- (4-methoxyphenyl) urea A solution of EXAMPLE 5B (44 mg, 0.077 mL) in tetrahydrofuran (2 mL) was treated with 2N HCl (1 mL), then stirred at room temperature for 18 hours. The resulting suspension was filtered and the solid was collected and dried to provide the title compound. 1 H NMR. (300 MHz, DMSO-de) d ppm 3.72 (s, 3H) 3.32-3.45 (m, 4 H) 3.84 - 3.91 (m, 1 H) 4.12 (dd, J = 13.90, 7.80 Hz, 1 H) 4.34 ( dd, J = 13.90, 3.73 Hz, 1 H) 6.89 (d, J = 9.15 Hz, 2 H) 6.89 - 6.93 (m, 2 H) 7.38 (d, J = 9.15 Hz, 2 H) 7.45 (d, J = 8.81 Hz, 2 H) 7.65 (d, J = 8.81 Hz, 2H) 7.94 (s, 1 H) 7.99 (d, J = 0.68 Hz, 1 H) 8.06 (s, 1 H) 8.28 (d, J = 0.68 Hz, 1 H) 8.72 (s, 1 H) 9.05 (s, 1 H); MS (ESI (+)) m / z 531.2 (M + H) +.

EXAMPLE 6 W-. { 4- [4-amino-7- (7H-pyrazol-4-yl) thieno [3,2-c] pyridin-3-yl) phenyl} -A / '- (3-methylphenol) urea Example 6 is described as EXAMPLE 703 in International Publication WO 2005/10009.

The foregoing is to illustrate the present invention and not to limit it. The variations and changes obvious to those skilled in the art are projected to be within the scope of the present invention, as defined by the appended claims.

Claims (5)

1. A compound that has the form or a therapeutically or acceptable salt thereof, wherein R is hydroxyalkyl; R2 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; Y R3 is hydrogen or alkyl.
2. 2. The compound as described in claim 1, characterized in that it is A- (4- { 4-amino-7- [1 - (2-hydroxy-1-yl) -1-pyrazol-4-yl] -thieno [3,2-c] pyridin-3-yl} phenyl) -N '- (3-fluorophenyl) urea; A / - (4- { 4-amino-7- [1 - (2-hyd roxy et i I) -1 H -pyrazol-4-yl] thieno [3,2-c | pyridin-3-yl] .}. phenyl) -A / '- [4- (difluoromethoxy) phenyl] urea; A / - [4- (4-amino-7- { 1 - [(2S) -2-hydroxypropyl] -1 H -pyrazol-4-yl.} Thieno [3,2-c] pyridin-3 -yl) phenyl] - / V '- (3-methylphenyl) urea; A / - (4- { 4-amino-7- [1- (2-hydroxy-2-methylpropyl) -1 / -pyrazol-4-yl] thieno [3,2-c] pyridin-3- il.) phenyl) -A / '- (4-methoxyphenyl) urea; Y / V- [4- (4-amino-7- { 1 - [(2S) -2,3-dihydroxypropyl] -1 H -pyrazol-4-yl} thieno [3,2-c] pyridine -3-yl) phenyl] -A / '- (4-methoxyphenyl) urea.
3. 3. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the compound does not inhibit CYP3A4.
4. 4. A composition comprising an excipient and a therapeutically effective amount of a compound as described in claim 1.
5. 5. A method for treating cancer in a mammal, wherein the method comprises administering thereto a therapeutically acceptable amount of a compound as described in claim 1.